Methods and devices for activating brown adipose tissue using electrical energy

ABSTRACT

Methods and devices are provided for activating brown adipose tissue (BAT). Generally, the methods and devices can activate BAT to increase thermogenesis, e.g., increase heat production in the patient, which over time can lead to weight loss. In one embodiment, a medical device is provided that activates BAT by electrically stimulating nerves that activate the BAT and/or electrically stimulating brown adipocytes directly, thereby increasing thermogenesis in the BAT and inducing weight loss through energy expenditure.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. application Ser. No.14/700,611 filed Apr. 30, 2015 entitled “Methods And Devices ForActivating Brown Adipose Tissue Using Electrical Energy,” which is acontinuation of U.S. application Ser. No. 12/980,659 filed Dec. 29, 2010entitled “Methods And Devices For Activating Brown Adipose Tissue UsingElectrical Energy” (now U.S. Pat. No. 9,044,606), which claims priorityto U.S. Provisional Application Ser. No. 61/297,405 filed Jan. 22, 2010entitled “Methods And Devices For Activating Brown Adipose Tissue,”which are hereby incorporated by reference in their entireties.

U.S. application Ser. No. 12/980,659 was concurrently filed on Dec. 29,2010 with U.S. application Ser. No. 12/980,635 entitled “DiagnosticMethods And Combination Therapies Involving MC4R,” which claims thepriority of U.S. Provisional Application Ser. No. 61/297,483 entitled“Diagnostic Methods And Combination Therapies Involving MC4R,” which arehereby incorporated by reference herein in their entireties.

FIELD OF THE INVENTION

The present invention relates to methods and devices for inducing weightloss, and in particular to methods and devices for activating brownadipose tissue using electrical energy.

BACKGROUND OF THE INVENTION

Obesity is becoming a growing concern, particularly in the UnitedStates, as the number of people with obesity continues to increase andmore is learned about the negative health effects of obesity. Severeobesity, in which a person is 100 pounds or more over ideal body weight,in particular poses significant risks for severe health problems.Accordingly, a great deal of attention is being focused on treatingobese patients.

Surgical procedures to treat severe obesity have included various formsof gastric and intestinal bypasses (stomach stapling), biliopancreaticdiversion, adjustable gastric banding, vertical banded gastroplasty,gastric plications, and sleeve gastrectomies (removal of all or aportion of the stomach). Such surgical procedures have increasingly beenperformed laparoscopically. Reduced postoperative recovery time,markedly decreased post-operative pain and wound infection, and improvedcosmetic outcome are well established benefits of laparoscopic surgery,derived mainly from the ability of laparoscopic surgeons to perform anoperation utilizing smaller incisions of the body cavity wall. However,such surgical procedures risk a variety of complications during surgery,pose undesirable post-operative consequences such as pain and cosmeticscarring, and often require lengthy periods of patient recovery.Patients with obesity thus rarely seek or accept surgical intervention,with only about 1% of patients with obesity being surgically treated forthis disorder. Furthermore, even if successfully performed and initialweight loss occurs, surgical intervention to treat obesity may notresult in lasting weight loss, thereby indicating a patient's need foradditional, different obesity treatment.

Nonsurgical procedures for treating obesity have also been developed.However, effective therapies for increasing energy expenditure and/oraltering a patient's metabolism, e.g., a basal metabolic rate, leadingto improvements in metabolic outcomes, e.g., weight loss, have focusedon pharmaceutical approaches, which have various technical andphysiological limitations.

It has been recognized in, for example, U.S. Pat. No. 6,645,229 filedDec. 20, 2000 and entitled “Slimming Device,” that brown adipose tissue(BAT) plays a role in the regulation of energy expenditure and thatstimulating BAT can result in patient slimming. BAT activation isregulated by the sympathetic nervous system and other physiological,e.g., hormonal and metabolic, influences. When activated, BAT removesfree fatty acids (FFA) and oxygen from the blood supply for thegeneration of heat. The oxidative phosphorylation cycle that occurs inthe mitochondria of activated BAT is shown in FIGS. 1 and 2.

Accordingly, there is a need for improved methods and devices fortreating obesity and in particular for activating BAT.

SUMMARY OF THE INVENTION

The present invention generally provides methods and devices foractivating brown adipose tissue using electrical energy. In oneembodiment, a medical method is provided that includes positioning adevice in contact with tissue of a patient proximate to a depot of brownadipose tissue, and activating the device to deliver an electricalsignal to the patient to activate the brown adipose tissue and increaseenergy expenditure of the brown adipose tissue. The electrical signalhas a modulating signal and a carrier signal. The carrier signal canhave any carrier frequency, such as a carrier frequency in a range ofabout 10 to 400 kHz, e.g., in a range of about 200 to 250 kHz. Themodulating signal can have any activation frequency, such as anactivation frequency in a range of about 0.1 to 100 Hz, e.g., less thanabout 10 Hz.

The electrical signal can have a variety of characteristics. Forexample, the electrical signal can have a pulse width in a range ofabout 10 μs to 10 ms, a voltage having an amplitude in a range of about1 to 20 V, and/or a current having an amplitude in a range of about 2 to6 mA. The electrical signal can be delivered to the patient continuouslyfor a predetermined amount of time, e.g., at least four weeks. Thedevice can be configured to be in continuous direct contact with thetissue of the patient for at least one day with the device generatingthe electrical signal and continuously delivering the electrical signalto the patient for at least one day.

The depot of brown adipose tissue can be located anywhere in thepatient, such as in a supraclavicular region of the patient.

The device can have a variety of configurations. In some embodiments,the device can include a housing configured to be disposed in directcontact with the tissue of the patient proximate to the depot of brownadipose tissue, and a signal generator coupled to the housing andconfigured to generate the electrical signal and to deliver theelectrical signal to the patient. The signal generator can be locatedwithin the housing. The housing can include a housing of a patchattached to the patient. The device can also include a controllerconfigured to turn the signal generator on to start the signal generatorgenerating the electrical signal, turn the signal generator off to stopthe signal generator from generating the electrical signal, or both. Thecontroller can be configured to be located remotely from the patient andto be in electronic communication with the signal generator, and/or thecontroller can be configured to be implanted entirely within thepatient.

The device can be positioned in contact with tissue of a patient in avariety of ways. For example, the device can be positioned in contactwith tissue of a patient by transcutaneously applying the device to anexterior skin surface of the patient. For another example, the devicecan be positioned in contact with tissue of a patient by subcutaneouslypositioning at least a portion of the device within the patient. In someembodiments, the device can be implanted entirely within the patient.For still another example, the device can be positioned proximate to atleast one of a supraclavicular region, a nape of a neck, a scapula, aspinal cord, proximal branches of the sympathetic nervous system thatterminate in BAT depots, and a kidney.

The medical method can also include removing the device from thepatient, repositioning the device in contact with tissue of the patientproximate to another depot of brown adipose tissue, and activating thedevice to deliver another electrical signal to the patient to activatethe other depot of brown adipose tissue and increase energy expenditureof the other depot of brown adipose tissue. The depot of brown adiposetissue can be in a supraclavicular region on one of a left and rightside of a sagittal plane of the patient, and the other depot of brownadipose tissue can be in a supraclavicular region on the other of theleft and right side of the sagittal plane of the patient. The device canbe removed and repositioned at any time, such as after the electricalsignal has been delivered to the depot of brown adipose tissue for athreshold amount of time, e.g., at least seven days. The device cancontinuously deliver the electrical signal to the patient during thethreshold amount of time. In some embodiments, in response to a triggerevent, the device can be removed from contact with tissue of the patientand repositioned to be in contact with another area of tissue of thepatient proximate to another depot of brown adipose tissue. The triggerevent can include at least one of the patient eating, the patientresting, a threshold temperature of the patient, a directionalorientation of the patient, a change in the patient's weight, a changein the patient's tissue impedance, manual activation by the patient orother human, a blood chemistry change in the patient, and a signal froma controller in electronic communication with the device.

In some embodiments, the method can include stopping application of theelectrical signal, waiting a predetermined amount of time, andactivating the device to deliver another electrical signal to thepatient to activate the depot of brown adipose tissue and increaseenergy expenditure of the brown adipose tissue. The stopping, thewaiting, and the activating can be repeated until occurrence of athreshold event. The threshold event can include, for example, at leastone of a predetermined amount of time and a predetermined physiologicaleffect.

The device can be activated to deliver an electrical signal to thepatient to activate the brown adipose tissue without cooling the patientor the brown adipose tissue and/or without any pharmaceuticaladministered to the patient to activate the brown adipose tissue.

The method can optionally include positioning a second device in contactwith tissue of the patient proximate to another depot of brown adiposetissue, and activating the second device to deliver a second electricalsignal to the patient to activate the other depot of brown adiposetissue and increase energy expenditure of the other depot of brownadipose tissue. The second device can deliver the second electricalsignal to the patient simultaneously with the device delivering theelectrical signal to the patient.

The method can have any number of variations. For example, the methodcan include reducing power of the electrical signal until a firstpredetermined threshold event occurs, and subsequently increasing thepower of the electrical signal until a second predetermined thresholdevent occurs. For another example, the device can be activated inresponse to a trigger event including at least one of the patienteating, the patient resting, a threshold temperature of the patient, adirectional orientation of the patient, a change in the patient'sweight, a change in the patient's tissue impedance, manual activation bythe patient or other human, a blood chemistry change in the patient, anda signal from a controller in electronic communication with the device.For still another example, the method can include imaging the patient tolocate the depot of brown adipose tissue prior to positioning the devicein contact with tissue of the patient proximate to the depot of brownadipose tissue.

In another embodiment, a medical method is provided that includespositioning a device in contact with tissue of a patient proximate to afirst depot of brown adipose tissue, activating the device to deliver afirst electrical signal to the patient to activate the first depot andincrease energy expenditure of the first depot, delivering the firstelectrical signal to the patient until a first threshold event occurs,when the first threshold event occurs, stopping delivery of the firstelectrical signal to the patient, delivering a second electrical signalto the patient to activate a second depot of brown adipose tissue andincrease energy expenditure of the second depot, delivering the secondelectrical signal to the patient until a second threshold event occurs,and when the second threshold event occurs, stopping delivery of thesecond electrical signal.

The first and second electrical signals can have a variety ofcharacteristics. For example, each of the first and second electricalsignals can have a modulating signal and a carrier signal. Themodulating signal can have an activation frequency in a range of about0.1 to 100 Hertz, and the carrier signal can have a carrier frequency ina range of about 10 to 400 kHz. For another example, the first andsecond electrical signals can be simultaneously delivered to thepatient. For still another example, the first and second electricalsignals can be sequentially delivered to the patient such that thepatient receives only one of the first and second electrical signals ata time. When the second threshold event occurs, the device in contactwith tissue of the patient proximate to the first depot can be activatedto deliver a third electrical signal to the patient to activate thefirst depot and increase energy expenditure of the first depot.

The first and second threshold events can vary, and they can be the sameas or different from one another. In some embodiments, the firstthreshold event can include passage of a first predetermined amount oftime, and the second threshold event can include passage of a secondpredetermined amount of time. The first and second predetermined amountsof time can also vary, and they can also be the same as or differentfrom one another. For example, the first and second predeterminedamounts of time can each be at least about 24 hours, e.g., can each beat least about seven days.

The first and second depots of brown adipose tissue can be locatedanywhere in the patient, such as the first depot being located on one ofa left and right side of a sagittal plane of the patient, and the seconddepot being located on the other of the left and right sides of thesagittal plane of the patient.

The method can vary in any number of ways. For example, beforedelivering the second electrical signal to the patient, the device canbe repositioned to be in contact with tissue of the patient proximate tothe second depot and using the device to deliver the second electricalsignal to the patient. For another example, a second device can bepositioned in contact with tissue of the patient proximate to the seconddepot, and the second device can be used to deliver the secondelectrical signal to the patient.

In another aspect, a medical device is provided including a housingconfigured to be disposed in direct contact with a body of a patientproximate to brown adipose tissue, and a signal generator located withinthe housing and configured to generate an electrical signal and todeliver the electrical signal to the body of the patient to electricallystimulate the brown adipose tissue. The electrical signal can have avariety of configurations, e.g., have a voltage having an amplitude ofup to about 20 V, have an activation frequency in a range of about 5 to10 Hz, and have a carrier frequency in a range of about 200 to 250 kHz.

The housing, e.g., a housing of a patch attached to the patient, canhave a variety of sizes, shapes, and configurations. The housing can beconfigured to be applied to an exterior skin surface of the patient totranscutaneously deliver the electrical signal, e.g., using an electrodein direct contact with the exterior skin surface. In another embodiment,the housing can be configured to be at least partially implanted withinthe patient, e.g., implanted entirely within the patient, tosubcutaneously apply the electrical signal to the patient. The housingcan be configured to be in continuous direct contact with the body ofthe patient for at least one day with the signal generator generatingthe electrical signal and delivering the electrical signal to the bodyof the patient.

In some embodiments the medical device can also include a controllerconfigured to turn the signal generator on to start the signal generatorgenerating the electrical signal and/or turn the signal generator off tostop the signal generator from generating the electrical signal. Thecontroller can be configured to be located remotely from the patient andto be in electronic communication with the signal generator. Thecontroller can be configured to be implanted entirely within thepatient.

In another aspect, a medical method is provided that includespositioning a device in contact with tissue of a patient proximate to adepot of brown adipose tissue, and activating the device to deliver anelectrical signal to the patient to activate the brown adipose tissue,e.g., through sympathetic nerve stimulation and/or stimulating brownadipocytes directly, and increase energy expenditure of the brownadipose tissue. Positioning the device in contact with tissue of thepatient can include transcutaneously applying the device to an exteriorskin surface of the patient or subcutaneously positioning the devicewithin the patient. In some embodiments, the patient can be imaged tolocate the depot of brown adipose tissue prior to positioning the devicein contact with tissue of the patient. The device can be positionedproximate to at least one of a nape of a neck, a scapula, a spinal cord,proximal branches of the sympathetic nervous system that terminate inBAT depots, and a kidney. In some embodiments, positioning a device incontact with tissue of a patient proximate to a depot of brown adiposetissue can include positioning the device proximate to a nerve that whendepolarized, leads to the activation of the brown adipose tissue. Theelectrical signal can have a variety of configurations, e.g., have avoltage having an amplitude of about 20 Volts, have an activation signalpulse frequency in a range of about 5 to 10 Hertz, and have a carrierfrequency in a range of about 200 to 250 kHz.

The method can vary in any number of ways. For example, the device canbe activated in response to a trigger event including at least one ofthe patient eating, the patient resting, a threshold temperature of thepatient, a directional orientation of the patient, a change in thepatient's weight, a change in the patient's tissue impedance, manualactivation by the patient or other human, a blood chemistry change inthe patient, and a signal from a controller in electronic communicationwith the device. For another example, the device can be activated todeliver an electrical signal to the patient to activate the brownadipose tissue without cooling the patient or the brown adipose tissueand/or without any pharmaceutical administered to the patient toactivate the brown adipose tissue. For yet another example, theelectrical signal can be continuously delivered to the patient for apredetermined amount of time, e.g., at least four weeks. For anotherexample, the method can include stopping application of the electricalsignal, waiting a predetermined amount of time, and activating thedevice to deliver another electrical signal to the patient to activatethe depot of brown adipose tissue and increase energy expenditure of thebrown adipose tissue. The stopping, the waiting, and the activating canbe repeated until occurrence of a threshold event, e.g., at least one ofa predetermined amount of time and a predetermined physiological effectsuch as a predetermined amount of weight lost by the patient. Foranother example, the method can include reducing the power of theelectrical signal until a first predetermined threshold event occurs(e.g., until a first predetermined period of time passes), andsubsequently increasing the power of the electrical signal until asecond predetermined threshold event occurs (e.g., until a secondpredetermined period of time passes, which can be the same or differentfrom the first predetermined period of time). For yet another example, asecond device can be positioned in contact with tissue of the patientproximate to another depot of brown adipose tissue, and the seconddevice can be activated to deliver a second electrical signal to thepatient to activate the other depot of brown adipose tissue and increaseenergy expenditure of the other depot of brown adipose tissue. Thesecond device can deliver the second electrical signal to the patientsimultaneously with the device delivering the electrical signal to thepatient.

In some embodiments, the method can also include removing the devicefrom the patient, repositioning the device in contact with tissue of thepatient proximate to another depot of brown adipose tissue, andactivating the device to deliver another electrical signal to thepatient to activate the other depot of brown adipose tissue, e.g.,through sympathetic nerve stimulation and/or direct stimulation of brownadipocytes, and increase energy expenditure of the other depot of brownadipose tissue. The device can be removed and repositioned after theelectrical signal has been delivered to the depot of brown adiposetissue for a threshold amount of time, e.g., at least seven days.Alternatively or in addition, the device can be removed and repositionedin response to a trigger event including at least one of the patienteating, the patient resting, a threshold temperature of the patient, adirectional orientation of the patient, a change in the patient'sweight, a change in the patient's tissue impedance, manual activation bythe patient or other human, a blood chemistry change in the patient, anda signal from a controller in electronic communication with the device.

In another embodiment, a medical method is provided that includespositioning a device on a body of a patient, e.g., on skin of thepatient, generating an electrical signal with the device, and targetingthe electrical signal to stimulate a tissue that regulates energyexpenditure within the patient. At least a portion of the electricalsignal can be periodic. At least a portion of the device can bepositioned subcutaneously within the patient.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be more fully understood from the following detaileddescription taken in conjunction with the accompanying drawings, inwhich:

FIG. 1 is a schematic view of an oxidative phosphorylation cycle thatoccurs in mitochondria within BAT cells;

FIG. 2 is a schematic view of BAT mitochondria showing an oxidativephosphorylation cycle that occurs in the mitochondria;

FIG. 3 is a schematic view of PET-CT images showing the locations of BATdepots in a patient subject to a cold environment and in the patient ina normal, warm environment;

FIG. 4 is a transparent view of a portion of a human neck, chest, andshoulder area with a shaded supraclavicular region;

FIG. 5 is a graph showing voltage v. time for a generic electricalsignal;

FIG. 6 is a graph showing total energy expenditure v. time for anexperimental, continuous, direct electrical signal delivered to BATdepots in a group of subjects and showing total energy expenditure v.time for a group of non-stimulated control subjects;

FIG. 7 is a graph showing a first plot of oxygen consumption v. time forthe experimental, continuous, direct electrical signal delivered to BATdepots in the group of subjects of FIG. 6 and showing oxygen consumptionv. time for the group of non-stimulated control subjects of FIG. 6, andshowing a second plot of cumulative food intake v. time for theexperimental, continuous, direct electrical signal delivered to BATdepots in the group of subjects of FIG. 6 and showing cumulative foodintake v. time for the group of non-stimulated control subjects of FIG.6;

FIG. 8 is a graph showing body weight v. time for the experimental,continuous, direct electrical signal delivered to BAT depots in thegroup of subjects of FIG. 6 and showing body weight v. time for thegroup of non-stimulated control subjects of FIG. 6;

FIG. 9 is a graph showing BAT temperature v. time for an experimental,intermittent, direct electrical signal delivered to BAT depots in onesubject;

FIG. 10 is a graph showing BAT and core temperatures v. time for anexperimental, intermittent, direct electrical signal delivered to BATdepots in one subject;

FIG. 11 is a graph showing voltage v. time for a generic electricalsignal including a low frequency modulating signal and a high frequencycarrier signal;

FIG. 12 is a front view of a body showing one embodiment of anelectrical stimulation device positioned on opposite sides of the body'ssagittal plane;

FIG. 13 is a schematic view of one embodiment of a transcutaneous devicefor stimulating BAT;

FIG. 14 is a plurality of graphs showing exemplary waveforms generatedby the transcutaneous device of FIG. 13;

FIG. 15 is a schematic view of one embodiment of an implantable devicefor stimulating BAT; and

FIG. 16 is a plurality of graphs showing exemplary waveforms generatedby the implantable device of FIG. 15.

DETAILED DESCRIPTION OF THE INVENTION

Certain exemplary embodiments will now be described to provide anoverall understanding of the principles of the structure, function,manufacture, and use of the devices and methods disclosed herein. One ormore examples of these embodiments are illustrated in the accompanyingdrawings. Those skilled in the art will understand that the devices andmethods specifically described herein and illustrated in theaccompanying drawings are non-limiting exemplary embodiments and thatthe scope of the present invention is defined solely by the claims. Thefeatures illustrated or described in connection with one exemplaryembodiment may be combined with the features of other embodiments. Suchmodifications and variations are intended to be included within thescope of the present invention.

Various exemplary methods and devices are provided for activating brownadipose tissue (BAT) using electrical energy. In general, the methodsand devices can activate BAT to increase thermogenesis, e.g., increaseheat production and energy expenditure in the patient, which over timecan lead to one or more of weight loss, a change in the metabolism ofthe patient, e.g., increasing the patient's basal metabolic rate, andimprovement of comorbidities associated with obesity, e.g., Type IIdiabetes, high blood pressure, etc. In an exemplary embodiment, amedical device is provided that activates BAT by electricallystimulating nerves that activate the BAT and/or electrically stimulatingbrown adipocytes directly, thereby increasing thermogenesis in the BATand inducing weight loss through energy expenditure. In this way, weightloss can be induced without performing a major surgical procedure,without relying on administration of one or more pharmaceuticals,without relying on cooling of the patient, and without surgicallyaltering a patient's stomach and/or other digestive organs.

Following a surgical procedure to treat obesity such as Roux-en-Ygastric bypass (RYGB), a patient can lose weight due to an increase inenergy expenditure, as demonstrated in a rodent model for example inStylopoulos et al., “Roux-en-Y Gastric Bypass Enhances EnergyExpenditure And Extends Lifespan In Diet-Induced Obese Rats,” Obesity 17(1 Oct. 2009), 1839-47. Additional data from Stylopoulos et al. (notpublished in the previous article or elsewhere as of the filing date ofthe present non-provisional application) indicates that RYGB is alsoassociated with increased levels of uncoupling protein 1 (UCP1), whichis an uncoupling protein in mitochondria of BAT, as well as with asignificant reduction in the size of fat stores within BAT and anincreased volume of BAT. It thus appears that RYGB causes activation ofBAT, although as discussed above, surgical procedures to treat obesity,such as gastric bypass, risk if not necessarily cause a variety ofundesirable results. Devices and methods to activate BAT without a majorsurgical procedure like RYGB but instead with electrical nervestimulation to increase energy expenditure are therefore provided.

One characteristic of BAT that distinguishes it from white adiposetissue (WAT) stores is the high number of mitochondria in a single BATcell. This characteristic makes BAT an excellent resource for burningenergy. Another distinguishing characteristic of BAT is that whenactivated, UCP1 is utilized to introduce inefficiency into the processof adenosine triphosphate (ATP) creation that results in heatgeneration. Upregulation of UCP1 is therefore a marker of BATactivation.

Activation of brown adipocytes leads to mobilization of fat storeswithin these cells themselves. It also increases transport of FFA intothese cells from the extracellular space and bloodstream. FFAs in theblood are derived primarily from fats metabolized and released fromadipocytes in WAT as well as from ingested fats. Stimulation of thesympathetic nervous system is a major means of physiologicallyactivating BAT. Sympathetic nerve stimulation also induces lipolysis inWAT and release of FFA from WAT into the bloodstream to maintain FFAlevels. In this way, sympathetic stimulation leads ultimately to thetransfer of lipids from WAT to BAT followed by oxidation of these lipidsas part of the heat generating capacity of BAT.

The controlled activation of BAT can be optimized, leading to weightloss, by reducing the stores of triglycerides in WAT. A person skilledin the art will appreciate that exposure to cold temperature leads tothe activation of BAT to help regulate body temperature. This knowledgeallows the location of BAT to be readily assessed using positronemission tomography-computed tomography (PET-CT) imaging. FIG. 3 showsscans of a patient subjected to a cold environment (left two images) andthe same patient scanned in a normal, warm environment (right twoimages). Shown in black are regions of intense glucose uptake—namely,the brain, the heart, the bladder, and in the cold environment, BAT.However these images show the locations of BAT depots—namely the nape ofthe neck, the supraclavicular region, over the scapula, alongside thespinal cord, and around the kidneys as referenced by, for example,Rothwell et al, “A Role For Brown Adipose Tissue In Diet-InducedThermogenesis,” Nature, Vol. 281, 6 Sep. 1979, and Virtanen et al.,“Functional Brown Adipose Tissue in Healthy Adults,” The New EnglandJournal of Medicine, Vol. 360, No. 15, Apr. 9, 2009, 1518-1525.

A person skilled in the art will appreciate that adult humans havesubstantial BAT depots, as indicated, for example, in J. M. Heaton, “TheDistribution Of Brown Adipose Tissue In The Human,” J Anat., 1972 May,112(Pt 1): 35-39, and W. D. van Marken Lichtenbelt et al,“Cold-Activated Brown Adipose Tissue in Healthy Men,” N. Engl. J. Med.,2009 April, 360, 1500-1508. A person skilled in the art will alsoappreciate that BAT is heavily innervated by the sympathetic nervoussystem, as indicated, for example, in Lever et al., “Demonstration Of ACatecholaminergic Innervation In Human Perirenal Brown Adipose Tissue AtVarious Ages In The Adult,” Anat Rec., 1986 July, 215(3): 251-5, 227-9.Further, “[t]he thin unmyelinated fibers that contain norepinephrine(and not NPY) are those that actually innervate the brown adipocytesthemselves. They form a dense network within the tissue, being incontact with each brown adipocyte (bouton-en-passant), and their releaseof norepinephrine acutely stimulates heat production and chronicallyleads to brown adipose tissue recruitment”. B. Cannon, and J.Nedergaard, “Brown Adipose Tissue: Function And PhysiologicalSignificance,” Physiol Rev., 2004: 84: 277-359.

Nerves innervating BAT can be stimulated to activate UCP1 and henceincrease energy expenditure through heat dissipation throughtranscutaneous and/or direct stimulation of nerves innervating BAT.Transcutaneous and direct stimulation are each discussed below in moredetail.

In some embodiments, transcutaneous and/or direct stimulation of nervesinnervating BAT can be combined with one or more treatments, beforeand/or after transcutaneous and/or direct stimulation of BAT, which canhelp encourage BAT stimulation and/or increase an amount of BAT in apatient. For non-limiting example, a pharmaceutical can be administeredto a patient, the patient can be cooled, the patient can be heated, amagnetic field can be targeted to a region of a patient, aBAT-stimulation procedure can be performed on the patient directed to aBAT depot and/or to a nerve innervating BAT, the patient can engage inweight loss therapies, and/or a surgical procedure can be performed onthe patient, such as a procedure to induce weight loss and/or to improvemetabolic function, e.g., glucose homeostatis, lipid metabolism, immunefunction, inflammation/anti-inflammatory balance, etc. A non-limitingexample of cooling the patient includes applying a cold pack to skin ofthe patient for a period of time. The cold pack can be applied to aregion of the skin with a high concentration of cold receptors, such asnear the wrists, ankles, and/or regions having thermosensitive transientreceptor potential (TRP) channels (e.g., TRPA1, TRPV1, TRPM8, etc.).Alternatively or in addition, the cold pack can be applied to the skinproximate to a BAT depot and/or to nerves innervating a BAT depot.Providing electrical stimulation, e.g., using an implanted electricalstimulation device, such that the BAT depot can be simultaneouslyactivated through a mechanism associated with a lowered body temperatureand electrically stimulated, thereby potentially further encouragingadditive or synergistic activation of the BAT. Non-limiting examples ofa nerve stimulation technique configured to stimulate a nerveinnervating BAT include delivery of a medium to the nerve that inducesan action potential in the nerve, e.g., electricity, light, mechanicalmanipulation or vibration, a magnetic field, a chemical substance, etc.Non-limiting examples of a BAT-stimulation procedure include inducingdifferentiation of muscle, WAT, preadipocytes, or other cells to BAT,and/or implanting or transplanting BAT cells into a patient.Non-limiting examples of implanting or transplanting BAT cells includeremoving cells from a patient, culturing the removed cells, andreimplanting the cultured cells; transplanting cells from anotherpatient; implanting cells grown from embryonic stem cells, adult stemcells, or other sources; and genetically, pharmacologically, orphysically altering cells to improve cell function. Non-limitingexamples of such weight loss therapies include a prescribed diet andprescribed exercise. Non-limiting examples of such a surgical procedureinclude gastric bypass, biliopancreatic diversion, vertical sleevegastrectomy, adjustable gastric banding, vertical banded gastroplasty,intragastric balloon therapy, gastric plication, Magenstrasse and Mill,small bowel transposition, biliary diversion, vagal nerve stimulation,duodenal endoluminal barrier, and procedures that allow for removal offood from the stomach. Combining one or more treatments, particularly aweight loss therapy or a weight loss surgical procedure which does notactivate BAT, e.g., a procedure other than RYGB, biliopancreaticdiversion (BPD) with or without duodenal switch, or some duodenal orother intestinal barrier (e.g., a prescribed diet and/or exerciseprogram, adjustable gastric banding, vertical banded gastroplasty,sleeve gastrectomy, gastric plication, Magenstrasse and Mill,intragastric balloon therapy, some duodenal or other intestinal barrier,and small bowel transposition, with a means for acute or chronicactivation of BAT such as the nerve stimulation discussed herein, canresult in desirable patient outcomes through a combined approach.

Because BAT activation may lead to an increase in body temperaturelocally, regionally, or systemically, transcutaneous and/or directstimulation of nerves innervating BAT can be combined with one or moreheat dissipation treatments, before and/or after transcutaneous and/ordirect stimulation of BAT. Non-limiting examples of such a heatdissipation treatment include inducing cutaneous/peripheralvasodilation, e.g., local or systemic administration of Alphaantagonists or blockers, direct thermal cooling, etc.

Whether BAT is activated directly and/or transcutaneously, target areasfor BAT nerve stimulation and/or direct stimulation of brown adipocytescan include areas proximate to BAT depots, e.g., a supraclavicularregion, the nape of the neck, over the scapula, alongside the spinalcord, near proximal branches of the sympathetic nervous system thatterminate in BAT depots, and around at least one of the kidneys. Any BATdepot can be selected for activation. For non-limiting example, in oneembodiment illustrated in FIG. 4, the device (not shown) can bepositioned proximate to an area over a scapula in a supraclavicularregion S. Identification of one or more BAT depots for activation can bedetermined on an individualized patient basis by locating BAT depots ina patient by imaging or scanning the patient using PET-CT imaging,tomography, thermography, or any other technique, as will be appreciatedby a person skilled in the art. Non-radioactive based imaging techniquescan be used to measure changes in blood flow associated with theactivation of BAT within a depot. In one embodiment, a contrast mediacontaining microbes can be used to locate BAT. The contrast media can beinjected into a patient whose BAT has been activated. An energy sourcessuch as low frequency ultrasound can be applied to the region ofinterest to cause destruction of bubbles from the contrast media. Therate of refill of this space can be quantified. Increased rates ofrefill can be associated with active BAT depots. In another embodiment,a contrast media containing a fluorescent media can be used to locateBAT. The contrast media can be injected into a patient whose BAT hasbeen activated. A needle based probe can be placed in the region ofinterest that is capable of counting the amount of fluorescent contrastthat passes the probe. Increased counts per unit time correspond toincreased blood flow and can be associated with activated BAT depots.Because humans can have a relatively small amount of BAT and because itcan be difficult to predict where BAT is most prevalent even near atypical BAT depot such as the nape of the neck, imaging a patient tomore accurately pinpoint BAT depots can allow more nerves innervatingBAT to be stimulated and with greater precision. Any number of BATdepots identified through patient imaging can be marked for futurereference using a permanent or temporary marker. As will be appreciatedby a person skilled in the art, any type of marker can be used to mark aBAT depot, e.g., ink applied on and/or below the epidermis, a dyeinjection, etc. The marker can be configured to only be visible underspecial lighting conditions such as an ultraviolet light, e.g., a blacklight.

Whether BAT is activated directly and/or transcutaneously, targetcellular areas for BAT nerve stimulation and/or direct stimulation ofbrown adipocytes can include cell surface receptors (e.g., TGR5, β₁AR,β₂AR, (β₃AR, etc.), nuclear receptors (e.g., PPARγ, FXR, RXR, etc.),transcription co-activators and co-repressors (e.g., PGC1α, etc.),intracellular molecules (e.g., 2-deiodinase, MAP kinase, etc.), UCP1activators, individual cells and related components (e.g., cell surface,mitochondria, and organelles), transport proteins, PKA activity,perilipin and HSL (phospho PKA substrate), CREBP (cAMP responseelement-binding protein), adenosine monophosphate-activated proteinkinase (AMPK), bile acid receptors (e.g., TGR5, FGF15, FXR, RXR α,etc.), muscarinic receptors, etc.

In the course of treating a patient, BAT nerves and/or brown adipocytescan be stimulated at any one or more BAT depots directly or indirectlyand can be stimulated simultaneously, e.g., two or more BAT depots beingconcurrently stimulated, or stimulated sequentially, e.g., different BATdepots being stimulated at different times. Simultaneous stimulation ofBAT can help encourage more and/or faster energy expenditure. Sequentialstimulation of BAT can help prevent the “burning out” of target nervesand can help stimulate the creation of new BAT cells. Sequential nervestimulation can include stimulating the same BAT depot more than once,with at least one other BAT depot being activated before activating apreviously activated BAT depot. Simultaneous and/or sequentialstimulation can help prevent tachypylaxis.

The electrical signal, whether transcutaneously or directly delivered,can be configured in a variety of ways. The stimulation “on” timeamplitude can be higher for shorter periods and increased or decreasedfor longer periods of application. The electrical signal can have any“geometry” of the applied voltage, e.g., square waves, ramp waves, sinewaves, triangular waves, and waveforms that contain multiple geometries.FIG. 5 illustrates amplitude, pulse width, activation signal pulsefrequency, duration of signal train, and a time between start of signaltrains for a generic (without any specified numerical parameters)electrical signal. In an exemplary embodiment, an electrical signaldelivered to BAT can have a voltage having an amplitude in a range ofabout 1 to 20 V, e.g., about 10 V, e.g., about 4 V, about 7 V, etc.; acurrent having an amplitude in a range of about 2 to 6 mA, e.g., about 3mA; a pulse width in a range about 10 μs to 40 ms, e.g., about 0.1 ms,about 2 ms, about 20 ms, etc.; an activation signal pulse frequency in arange of about 0.1 to 40 Hz, e.g., about 6 Hz or in a range of about 1to 20 Hz; and a duration of signal train in a range of about 1 second tocontinuous, e.g., about 30 seconds, etc. A time between start of signaltrains for a noncontinuous electrical signal delivered to BAT can be ofany regular, predictable duration, e.g., hourly, daily, coordinatedaround circadian, ultradian, or other cycles of interest, etc., such asabout ten minutes or about ninety minutes, or can be of any irregular,unpredictable duration, e.g., in response to one or more predeterminedtrigger events, as discussed further below.

In one non-limiting example, an electrical signal continuously deliveredto BAT can be a pulse having an amplitude of about 7 V, a pulse width ofabout 0.1 ms, an activation signal pulse frequency of about 6 Hz. FIG. 6shows one example of a graph of total energy expenditure v. time ofcontinuous direct delivery of this electrical signal via implanteddevice to an interscapular BAT depot over a period of five days. Resultsof electrical stimulation using this electrical signal is shown by thegraph line beginning at about 970 at Day 1, and a control ofnon-electrical stimulation is shown by the graph line beginning at about900 at Day 1. As illustrated in the graph, the electrical signaldelivery can lead to a sustained increase in oxygen consumption, whichis correlated with increases in energy expenditure in the subjects,which are rats in the illustrated example. Over time, the increases inenergy expenditure can lead to weight loss. Activity of the subjectsreceiving this electrical signal over the five day period was observedto be similar to activity of the subjects not receiving electricalstimulation over the five day period, thereby indicating that theillustrated increased energy expenditure of the stimulated subjects wasdue to the electrical stimulation and not due to increased physicalactivity and that the subjects were behaving normally during thestimulation treatment.

Oxygen consumption is plotted versus time for a 48 hour period in oneexample of a graph in FIG. 7 in which measurements were taken every 10minutes. In the top plot in FIG. 7, results of electrical stimulationusing this electrical signal are shown by the graph line beginning atabout 825 at time zero, and a control of non-electrical stimulation isshown by the graph line beginning at about 800 at time zero. In thebottom plot of FIG. 7, results of electrical stimulation using thiselectrical signal are shown by the graph line which is at about 9 g atan end of the 48 time period, and a control of non electricalstimulation is shown by the graph line which is at about 11 g at the endof the 48 time period. Sustained moderate increases in energyexpenditure were present for the electrically stimulated animals in thetwo light time periods, e.g., times when the animals were at rest, whilemore pronounced increases in energy expenditure were present for theelectrically stimulated animals in the two dark time periods, e.g., whenthe animals were active and eating. Thus, when subjects stimulated withthis electrical signal were active and eating, energy expenditureincreased substantially, whereas moderate increases were observed atrest. Such an increase is consistent with diet-induced thermogenesis.The increase also demonstrates that continuous direct electricalstimulation can help ensure that at any time a subject eats, stimulatedBAT can be ready to take the consumed calories and turn them into heat,thereby encouraging weight loss over time, as shown in one example of agraph in FIG. 8. Body weight is plotted versus time for a six weekperiod in FIG. 8, with time zero representing a time of surgery toimplant electrodes, which was performed on all subjects, and with weekthree marking a start time of electrical stimulation for the non-controlgroup subjects. Results of electrical stimulation using this electricalsignal are shown by the graph line beginning at about 550 g at timezero, and a control of non-electrical stimulation is shown by the graphline beginning at about 560 g at time zero. FIG. 8 illustrates that uponthe start of electrical stimulation of BAT at week three, theelectrically stimulated animals experienced continual weight loss untilat least week six. In contrast, the control, non-electrically stimulatedanimals gained weight during the same period starting at week three,resulting in a difference in weight of about 15 percent between thestimulated group and the non-stimulated group.

In another non-limiting example, an electrical signal delivered to BATcan be a pulse having an amplitude of about 4 V, a pulse width of about20 ms, an activation signal pulse frequency of about 6 Hz, a duration ofsignal train of about 30 seconds, and a time between start of signaltrains of about 10 minutes. FIG. 9 shows one example of a graph of BATtemperature in degrees Celsius v. time of intermittent direct deliveryof this electrical signal to a BAT depot of one patient. As illustratedin the graph, the electrical signal delivery can lead to a sustainedincrease in BAT temperature, which can be associated with a laggingincrease in core temperature of the subjects, which are rats in theillustrated example. Over time, the sustained increase in BATtemperature can lead to weight loss.

In another non-limiting example, an electrical signal delivered to BATcan be a pulse having an amplitude of about 10 V, a pulse width of about2 ms, an activation signal pulse frequency of about 6 Hz, a duration ofsignal train of about 30 seconds, and a time between start of signaltrains of about 10 minutes. FIG. 10 shows one example of a graph of BATtemperature v. time of intermittent direct delivery of this electricalsignal to a BAT depot of one patient during hours 5 and 6 of continuouselectrical signal delivery to subjects (rats in this illustratedexample). Core temperature is shown by the graph line beginning at about36.7° C. at time 5:15, and BAT temperature is shown by the graph linebeginning at about 35.3° C. at time 5:15. As illustrated in the graph,the electrical signal delivery can lead to a sustained activation ofBAT. Over time, the sustained activation of BAT can lead to weight loss.

In another non-limiting example, an electrical signal delivered to BATcan be configured as a monophasic square pulse having a square waveshape, a voltage alternating in amplitude from about 0 to 20 V, anactivation signal pulse frequency in a range of about 5 to 10 Hz, apulse width (duration) of about 2 ms, a pulse train on/off time of about20 seconds “on” and about 40 seconds “off,” and a treatment time ofabout 11 minutes, as described in more detail in Shimizu et al.,“Sympathetic Activation of Glucose Utilization in Brown Adipose Tissuein Rats,” Journal of Biochemistry, Vol. 110, No. 5, 1991, pgs 688-692.Further non-limiting examples of electrical signals that can bedelivered to BAT are described in more detail in Flaim et al.,“Functional and Anatomical Characteristics of the Nerve-Brown AdiposeInteration in the Rat,” Pflügers Arch., 365, 9-14 (1976); Minokoshi etal., “Sympathetic Activation of Lipid Synthesis in Brown Adipose Tissuein the Rat,” J. Psysio. (1988) 398, 361-70; Horwitz et al.,“Norepinephrine-Induced Depolarization of Brown Fat Cells.” Physiology(1969) 64, 113-20; and U.S. Pat. Pub. No. 2010/0312295 filed May 5, 2010entitled “Brown Adipose Tissue Utilization Through Neuromodulation.”

In one embodiment, the same electrical signal can be delivered to aparticular BAT depot, either continuously or sequentially. In anotherembodiment, a first electrical signal can be transcutaneously ordirectly delivered to a particular BAT depot, and then subsequently,either immediately thereafter or after a passage of a period of time, asecond, different electrical signal can be delivered to the sameparticular BAT depot. In this way, chances of a BAT depot adapting to aparticular electrical signal can be reduced, thereby helping to preventthe BAT depot from becoming less receptive to electrical stimulation.

Whether a continuous electrical signal or an intermittent electricalsignal is transcutaneously delivered, e.g., with a transdermal patch asdiscussed further below, or subcutaneously delivered via an at leastpartially implanted device, the electrical signal can include a lowfrequency modulating signal and a high frequency carrier signal.Generally, the high frequency carrier signal can be used to pass throughhigh impedance tissue (subcutaneous or transcutaneous) while themodulating signal can be used to activate nervous tissue and/orelectrically responsive brown adipocytes. The waveform can be generatedby modulating a carrier waveform with a pulse envelope. Properties ofthe carrier waveform such as amplitude, frequency, and the like, can bechosen so as to overcome the tissue impedance and the stimulationthreshold of the target nerve. The pulse envelope can be a waveformhaving a specific pulse width, amplitude and shape designed toselectively stimulate the target nerve. This waveform can be able topenetrate efficiently through tissue, such as skin, to reach the targetnerve with minimal loss in the strength of the electrical signal,thereby saving battery power that would otherwise have been used inseveral attempts to stimulate the target nerve with low frequencysignals. Moreover, only the target nerve is stimulated, and non-targetnerves, e.g., nerves associated with pain, are not stimulated. Exemplaryembodiments of methods and devices for applying a signal including ahigh frequency carrier signal are described in more detail in U.S. Pat.Pub. No. 2009/0093858 filed Oct. 3, 2007 and entitled “Implantable PulseGenerators And Methods For Selective Nerve Stimulation,” U.S. Pat. Pub.No. 2005/0277998 filed Jun. 7, 2005 and entitled “System And Method ForNerve Stimulation,” and U.S. Pat. Pub. No. 2006/0195153 filed Jan. 31,2006 and entitled “System And Method For Selectively StimulatingDifferent Body Parts.”

The low frequency modulating signal and a high frequency carrier signalcan each have a variety of values and configurations. The low frequencymodulating signal can be, e.g., a signal having an activation signalpulse frequency in a range of about 0.1 to 100 Hz, e.g., in a range ofabout 0.1 to 40 Hz, e.g., less than about 10 Hz. The high frequencycarrier signal can be, e.g., in a range of about 10 to 400 kHz, e.g., ina range of about 200 to 250 kHz. Pulse widths can also vary, e.g., be ina range of about 10 μs to 10 ms, e.g., less than about 2 ms. In oneexemplary embodiment, the electrical signal can have a modulating signalin a range of about 2 to 15 Hz, e.g., about 6 Hz, a carrier frequency ofabout 210 kHz, and a pulse width in a range of about 0.1 to 2 ms. FIG.11 illustrates a generic (without any specified numerical parameters)electrical signal including a low frequency modulating signal L and ahigh frequency carrier signal H.

Generally, low frequency signals can cause activation of Types A and Bfibers, e.g., myelinated neurons, and Type C fibers, e.g., unmyelinatedneurons. The signal to activate Type C fibers can be greater than, e.g.,a longer pulse width and a higher current amplitude, than a signal toactivate Type A and B fibers. Postganglionic fibers innervating BATdepots likely include Type C fibers, thereby allowing a BAT depot to beactivated by a low frequency signal, e.g., a signal less than about 10Hz and having a pulse width greater than about 300 μs. Preganglionicnerves such as small diameter, unmyelinated Type C fibers and smalldiameter, myelinated Type B fibers may also innervate BAT, thereby alsoallowing a BAT depot to be activated by a low frequency signal, e.g., asignal in a range of about 10 to 40 Hz and having a pulse width lessthan about 200 μs.

An electrical signal delivered to a BAT depot can be appliedcontinuously, in predetermined intervals, in sporadic or randomintervals, in response to one or more predetermined trigger events, orin any combination thereof. If the signal is continuously delivered tothe patient, particular care should be taken to ensure that the signaldelivered to the patient will not damage the target nerves or tissues.For one non-limiting example, nerve or tissue damage can be reduced, ifnot entirely prevented, by continuously delivering an electrical signalvia en electrode having a relatively large surface area to helpdistribute an electrical signal's energy between multiple nerves. Forelectrical signals delivered intermittently, nerve damage can bereduced, if not entirely prevented, by selecting an on/off ratio inwhich the signal is “off” for more time than it is “on.” Fornon-limiting example, delivering an electrical signal to BATintermittently with an on/off ratio of about 1:19, e.g., electricalsignals delivered for 30 seconds every ten minutes (30 seconds on/9.5minutes off), can help reduce or entirely prevent nerve damage. Thedevice delivering the electrical signal can be configured to respond toone or more predetermined trigger events, e.g., events that are sensedby or otherwise signaled to the device. Non-limiting examples of triggerevents include the patient eating, the patient resting (e.g., sleeping),a threshold temperature of the patient (e.g., a temperature in thestimulated BAT depot or a core temperature), a directional orientationof the patient (e.g., recumbent as common when sleeping), a change inthe patient's weight, a change in the patient's tissue impedance, manualactivation by the patient or other human (e.g., via an onboardcontroller, via a wired or wirelessly connected controller, or upon skincontact), a blood chemistry change in the patient (e.g., a hormonalchange), low energy expenditure, menstrual cycles in women, medicationintake (e.g., an appetite suppressant such as topiramate, fenfluramine,etc.), an ultradian or other circadian rhythm of the patient, and amanually-generated or automatically-generated signal from a controllerin electronic communication, wired and/or wireless, with the device. Inone embodiment, the patient eating can be determined through a detectionof heart rate variability, as discussed in more detail in U.S. patentapplication Ser. No. 12/980,965 filed on Dec. 29, 2010 and entitled“Obesity Therapy And Heart Rate Variability” and U.S. patent applicationSer. No. 12/980,710 filed on Dec. 29, 2010 and entitled “Obesity TherapyAnd Heart Rate Variability”. The controller can be internal to thedevice, be located external from but locally to device, or be locatedexternal and remotely from device. As will be appreciated by a personskilled in the art, the controller can be coupled to the device in anyway, e.g., hard-wired thereto, in wireless electronic communicationtherewith, etc. In some embodiments, multiple devices can be applied apatient, and at least two of those devices can be configured to deliveran electrical signal based on different individual trigger events orcombinations of trigger events.

Generally, transcutaneous stimulation of BAT can include applying adevice to an exterior skin surface of a patient proximate to a BAT depotand activating the device to deliver an electrical signal to the BATdepot. In this way, the electrical signal can activate the BAT proximateto the device by stimulating the nerves innervating the BAT and/or bystimulating brown adipocytes directly. As mentioned above, two or moretranscutaneous devices, same or different from one another, can besimultaneously applied to a patient, proximate to the same BAT depot orto different BAT depots. Although a patient can have two or moretranscutaneously applied devices and although the devices can beconfigured to simultaneously deliver electrical signals to BAT, thedevices can be configured such that only one delivers an electricalsignal at a time. As also mentioned above, a transcutaneous device canbe rotated to different BAT depots of a patient and deliver anelectrical signal to each of the BAT depots. Rotating a device betweentwo or more different locations on a patient's body and/or removing adevice from a patient when not in use can help prevent nerve or tissuedesensitization and/or dysfunction, can help reduce any adverse effectsof a device's attachment to the body, e.g., irritation from an adhesiveapplying a device to skin, and/or can help stimulate creation orreplication of new BAT in multiple locations on a patient's body. Fornon-limiting example, the device can be placed in varying positions onthe body to modulate the activity of different regions of BAT. In oneembodiment, the device can be worn on one side of the neck, e.g., theleft side, for a period of time and then on an opposite side of theneck, e.g., the right side, for the next time period, etc. In anotherembodiment, the device can be worn on an anterior side of a BAT depot,e.g., front of a left shoulder on one side of the patient's coronalplane, for a period of time and then on an opposite, posterior side ofthe BAT depot, e.g., back of the left shoulder on the opposite side ofthe patient's coronal plane, for the next period of time. In yet anotherembodiment, illustrated in FIG. 12, a device 10 can be worn proximate aBAT depot on one of a left and right side of a sagittal plane P in asupraclavicular region of a body 12 for a period of time and then thedevice 10 can be worn on the other of the left and right sides of thesagittal plane P in the supraclavicular region proximate to another BATdepot for the next period of time. Although the same device 10 is shownin FIG. 12 as being sequentially relocated to different tissue surfaceor skin positions on the body 12, as discussed herein, one or both ofthe devices can be implanted and/or two separate devices can be usedwith a patient such that a first device is positioned at one locationand a second device is positioned at a second, different location.

In one embodiment, a transcutaneous device can be positioned in a firstlocation on a patient, e.g., a left supraclavicular region, for a firstpredetermined period of time, e.g., one week, and then relocated to asecond location on the patient, e.g., a right supraclavicular region,for a second predetermined period of time, e.g., one week. The first andsecond predetermined periods of time can be the same as or differentfrom one another. The first and second locations can mirror each other,e.g., on left and rights of a sagittal plane of the patient, or they cannon-mirror images of one another. During the first predetermined periodof time, the device can be configured to cycle in a diurnal patternduring waking hours between being “on” to electrically stimulate thepatient, e.g., a 30 minute dose of electrical stimulation having any ofthe parameters discussed herein, and being “off” without deliveringelectrical stimulation to the patient, e.g., a one hour period of nostimulation. The electrical signal, e.g., an electrical signal includingmodulating and carrier signals, delivered when the device is “on” can becontinuous, can ramp up at a start of the “on” time to a predeterminedmaximum level, such as a level set by a physician during an initialpatient visit, can ramp down at an end of the “on” time, and can besubstantially constant between the ramp up and ramp down times. Thesignal can ramp up and down in any amount of time, e.g., in less thanabout five minutes. Such a cycle can be repeated about twelve time perday during each of the first and second predetermined periods of time,and during any subsequent periods of time, e.g., repeatedly switchingthe device every other week between the first and second locations.

In another embodiment, a transcutaneous device can be positioned on anexterior skin surface of a patient and be configured to electricallystimulate the patient in a natural mimicking pattern for a time periodof at least one week. The device can be relocated to a differentlocation on the patient's skin and stimulate the patient at thedifferent location in the natural mimicking pattern for another timeperiod of at least one week. The device can continue being located andrelocated for any number of weeks. The electrical stimulation caninclude a fixed carrier frequency and a variable modulating frequencyconfigured to vary based on nutrient and mechanoreceptors that indicatethe patient eating. In other words, the modulating frequency can mimicstomach distension of the patient.

In still another embodiment, a transcutaneous device can be positionedon an exterior skin surface of a patient and be configured tointermittently electrically stimulate the patient at a constantintensity, e.g., cycle between an “on” configuration delivering anelectrical signal at the constant intensity to the patient and an “off”configuration without delivering any electrical signal to the patient.The delivered electrical signal can ramp up at a start of an “on” timeperiod to the constant intensity, and can ramp down at an end of the“on” time period from the constant intensity. The signal can ramp up anddown in any amount of time, such as ramp up for about ¼ of a total “on”time, deliver the signal at the constant intensity for about ½ of thetotal “on” time, and ramp down for about ¼ of the total “on” time. Inone embodiment, the device can ramp up from about 0 Hz to about 20 Hz inabout 15 minutes, stimulate at about 20 Hz for about 35 minutes, andramp down from about 20 Hz to about 0 Hz in about 10 minutes for a total“on” time of about 50 minutes.

The transcutaneous device used to transcutaneously activate BAT can havea variety of sizes, shapes, and configurations. Generally, the devicecan be configured to generate and/or deliver an electrical signal totissue at predetermined intervals, in response to a manual trigger bythe patient or other human, in response to a predetermined triggerevent, or any combination thereof. As will be appreciated by a personskilled in the art, and as discussed in more detail above and in U.S.Pat. Pub. No. 2009/0093858 filed Oct. 3, 2007 and entitled “ImplantablePulse Generators And Methods For Selective Nerve Stimulation,” the bodyattenuates low frequency signals requiring a high frequency signal fortransdermal passage. This high-frequency or carrier signal, inconjunction with a modulating low frequency wave can be applied by thetranscutaneous device to stimulate the nerves innervating BAT for FFA orother lipid consumption leading to loss of body fat and body weight.

FIG. 13 illustrates one exemplary embodiment of a transcutaneous device200 in the form of a selective nerve stimulation patch housingconfigured to generate and deliver an electrical signal to tissue suchas BAT. The device 200 includes a circuitized substrate 202 configuredto generate electrical signals for stimulating tissue such as BAT. Thedevice 200 can include a suitable power source or battery 208, e.g., alithium battery, a first waveform generator 264, and a second waveformgenerator 266. The first and second waveform generators 264, 266 can beelectrically coupled to and powered by the battery 208. The waveformgenerators 264, 266 can be of any suitable type, such as those sold byTexas Instruments of Dallas, Tex. under model number NE555. The firstwaveform generator 264 can be configured to generate a first waveform orlow frequency modulating signal 268, and the second waveform generator266 can be configured to generate a second waveform or carrier signal270 having a higher frequency than the first waveform 268. As discussedherein, such low frequency modulating signals cannot, in and ofthemselves, pass through body tissue to effectively stimulate targetnerves. The second waveform 270 can, however, to overcome this problemand penetrate through body tissue. The second waveform 270 can beapplied along with the first waveform 268 to an amplitude modulator 272,such as the modulator having the designation On-Semi MC1496, which issold by Texas Instruments.

The modulator 272 can be configured to generate a modulated waveform 274that is transmitted to one or more electrodes 232 accessible at a bottomsurface of the circuitized substrate 202. Although FIG. 13 shows onlyone electrode 232, the device 200 can include two or more electrodes.The electrodes 232 can be configured to, in turn, apply the modulatedwaveform 274 to a target nerve to stimulate the target nerve. Asillustrated in FIGS. 13 and 14, the first waveform 268 can be a squarewave, and the second waveform 270 can be a sinusoidal signal. As will beappreciated by a person skilled in the art, modulation of the firstwaveform 268 with the second waveform 270 can results in a modulatedwaveform or signal 274 having the configuration shown in FIG. 14.Although the signals in FIG. 14 are illustrated as being biphasic, thesignals can be monophasic.

Various exemplary embodiments of transcutaneous devices configured toapply an electrical signal or other stimulation means to stimulatenerves are described in more detail in U.S. Pat. Pub. No. 2009/0132018filed Nov. 16, 2007 and entitled “Nerve Stimulation Patches And MethodsFor Stimulating Selected Nerves,” U.S. Pat. Pub. No. 2008/0147146 filedDec. 19, 2006 and entitled “Electrode Patch And Method ForNeurostimulation,” U.S. Pat. Pub. No. 2005/0277998 filed Jun. 7, 2005and entitled “System And Method For Nerve Stimulation,” U.S. Pat. Pub.No. 2006/0195153 filed Jan. 31, 2006 and entitled “System And Method ForSelectively Stimulating Different Body Parts,” U.S. Pat. Pub. No.2007/0185541 filed Aug. 2, 2006 and entitled “Conductive Mesh ForNeurostimulation,” U.S. Pat. Pub. No. 2006/0195146 filed Jan. 31, 2006and entitled “System And Method For Selectively Stimulating DifferentBody Parts,” U.S. Pat. Pub. No. 2008/0132962 filed Dec. 1, 2006 andentitled “System And Method For Affecting Gastric Functions,” U.S. Pat.Pub. No. 2008/0147146 filed Dec. 19, 2006 and entitled “Electrode PatchAnd Method For Neurostimulation,” U.S. Pat. Pub. No. 2009/0157149 filedDec. 14, 2007 and entitled “Dermatome Stimulation Devices And Methods,”U.S. Pat. Pub. No. 2009/0149918 filed Dec. 6, 2007 and entitled“Implantable Antenna,” U.S. Pat. Pub. No. 2009/0132018 filed Nov. 16,2007 and entitled “Nerve Stimulation Patches And Methods For StimulatingSelected Nerves,” U.S. patent application Ser. No. 12/317,193 filed Dec.19, 2008 and entitled “Optimizing The Stimulus Current In A SurfaceBased Stimulation Device,” U.S. patent application Ser. No. 12/317,194filed Dec. 19, 2008 and entitled “Optimizing Stimulation Therapy Of AnExternal Stimulating Device Based On Firing Of Action Potential InTarget Nerve,” U.S. patent application Ser. No. 12/407,840 filed Mar.20, 2009 and entitled “Self-Locating, Multiple Application, And MultipleLocation Medical Patch Systems And Methods Therefor,” U.S. patentapplication Ser. No. 12/605,409 filed Oct. 26, 2009 and entitled “OffsetElectrodes.”

In an exemplary embodiment, the transcutaneous device can include anelectrical stimulation patch configured to be applied to an externalskin surface and to deliver an electrical signal to tissue below theskin surface, e.g., to underlying BAT. The patch can be configured togenerate its own electrical signal with a signal generator and/or todeliver an electrical signal received by the patch from a source inelectronic communication with the patch. The device can be wireless andbe powered by an on-board and/or external source, e.g., inductive powertransmission. The patch can be attached to the skin in any way, as willbe appreciated by a person skilled in the art. Non-limiting examples ofpatch application include using a skin adhesive locally (e.g., on patchrim), using a skin adhesive globally (e.g., on skin-contacting surfacesof the patch), using an overlying support (e.g., gauze with tapededges), using an adherent frame allowing interchangeability (e.g., abrace or an article of clothing), being subdermally placed with wirelessconnectivity (e.g., Bluetooth) or transdermal electrodes, and using anycombination thereof. Electrodes can include receiver circuitryconfigured to interact with a controller in electronic communicationwith the electrodes such that the controller can control at least somefunctions of the electrodes, e.g., on/off status of the electrodes andadjustment of parameters such as amplitude, frequency, length of train,etc.

In use, and as mentioned above, an electrical stimulation patch can beworn continuously or intermittently as needed. In a transcutaneousapplication, a patch such as one described in previously mentioned U.S.Pat. Pub. No. 2009/0132018, can be designed to transmit through the skinusing a dual waveform approach employing a first waveform designed tostimulated a nerve coupled with a high frequency carrier waveform. Thepatch can be placed proximate to a BAT depot, such as over the leftsupraclavicular region of the patient's back, for a predetermined amountof time, e.g., twelve hours, one day, less than one week, seven days(one week), one month (four weeks), etc., and can continuously deliveran electrical signal to the BAT. As mentioned above, the BAT depot canbe identified by imaging the patient prior to application of the patchproximate to the BAT depot. Seven days is likely the longest period anadhesive can be made to stick to the skin of a patient withoutmodification and can thus be a preferable predetermined amount of timefor patches applied to skin with an adhesive. After the predeterminedamount of time, the patch can be removed by a medical professional orthe patient, and the same patch, or more preferably a new patch, can beplaced, e.g., on the right supraclavicular region of the patient's backfor another predetermined amount of time, which can be the same as ordifferent from the predetermined amount of time as the first patchapplied to the patient. This process can be repeated for the duration ofthe treatment, which can be days, weeks, months, or years. In someembodiments, the process can be repeated until occurrence of at leastone threshold event, e.g., a predetermined amount of time, apredetermined physiological effect such as a predetermined amount ofweight lost by the patient, etc. If the same patch is relocated from afirst region, e.g., the left supraclavicular region, to a second region,right supraclavicular region, the patch can be reconditioned afterremoval from the first region and prior to placement at the secondregion. Reconditioning can include any one or more actions, as will beappreciated by a person skilled in the art, such as replacing one ormore patch components, e.g., a battery, an adhesive, etc.; cleaning thepatch; etc.

To more accurately simulate a weight loss surgery that has a continuousor chronic effect on a patient for an extended period of time, the patchcan be placed on a patient and continuously or chronically deliver anelectrical signal thereto for an extended, and preferably predetermined,amount of time. In an exemplary embodiment, the predetermined amount oftime can be at least four weeks. The electrical signal can be deliveredto same BAT depot for the predetermined amount of time, or two or moredifferent BAT depots can be stimulated throughout the predeterminedamount of time, e.g., left and right supraclavicular regions beingstimulated for alternate periods of seven days to total one month ofpredetermined time. Continued or chronic nerve stimulation to activateBAT can increase BAT energy expenditure over time and potentially inducemore or faster weight loss than periodic or intermittent nervestimulation. The electrical signal can be the same or can vary duringthe amount of time such that the electrical signal is continuously andchronically applied to the patient to provide 24/7 treatment mimickingthe 24/7 consequences of surgery. The continuous amount of time thepatient is electrically stimulated can be a total amount of continuousactivation of any one BAT depot (e.g., activation of a single BATdepot), sequential activation of two or more BAT depots, simultaneousactivation of two or more BAT depots, or any combination thereof. Atotal amount of time of sequential activation of different BAT depotscan be considered as one extended amount of time despite different areasof BAT activation because activation of one BAT depot may cause thebrain to signal for BAT activation in other BAT depots.

Generally, direct activation of BAT can include implanting a devicebelow the skin surface proximate to a BAT depot, e.g., within a BATdepot, and activating the device to deliver an electrical signal to thenerves innervating the BAT depot and/or to brown adipocytes directly.BAT itself is densely innervated, with each brown adipocyte beingassociated with its own nerve ending, which suggests that stimulatingthe BAT directly can target many if not all brown adipocytes anddepolarize the nerves, leading to activation of BAT. The sympatheticnerves that innervate BAT can be accessed directly through standardsurgical techniques, as will be appreciated by a person skilled in theart. The device can be implanted on a nerve or placed at or near a nervecell's body or perikaryon, dendrites, telodendria, synapse, on myelinshelth, node of Ranvier, nucleus of Schwann, or other glial cell tostimulate the nerve. While implanting such a device can require asurgical procedure, such implantation is typically relatively short,outpatient, and with greatly reduced risks from longer and morecomplicated surgical procedures such as gastric bypass. In an exemplaryembodiment, a stimulation device with at least two electrodes can be atleast partially implanted in the patient, and more preferably entirelywithin the patient. A person skilled in the art will appreciate that anynumber of electrodes, e.g., one or more, can be at least partiallyimplanted in the patient. The leads of the at least one electrode can beimplanted in a location sufficiently close to the nerves innervating theBAT so that when activated, the signal sent through the at least oneelectrode is sufficiently transferred to adjacent nerves, causing thesenerves to depolarize. As mentioned above, electrodes can includereceiver circuitry configured to interact with a controller inelectronic communication with the electrodes such that the controllercan control at least some functions of the electrodes, e.g., on/offstatus of the electrodes and adjustment of parameters such as amplitude,frequency, length of train, etc.

FIG. 15 illustrates one exemplary embodiment of an implantable device100 configured to generate and deliver an electrical signal to tissuesuch as BAT. The implantable device 100 can include a housing 102coupled to a suitable power source or battery 104, such as a lithiumbattery, a first waveform generator 106, and a second waveform generator108. As in the illustrated embodiment, the battery 104 and first andsecond waveform generators can be located within the housing 102. Inanother embodiment, a battery can be external to a housing and be wiredor wirelessly coupled thereto. The housing 102 is preferably made of abiocompatible material. The first and second waveform generators 106,108 can be electrically coupled to and powered by the battery 104. Thewaveform generators 106, 108 can be of any suitable type, such as thosesold by Texas Instruments of Dallas, Tex. under model number NE555. Thefirst waveform generator 106 can be configured to generate a firstwaveform or low frequency modulating signal 108, and the second waveformgenerator 110 can be configured to generate a second waveform or carriersignal 112 having a higher frequency than the first waveform 108. Asdiscussed herein, such low frequency modulating signals cannot, in andof themselves, pass through body tissue to effectively stimulate targetnerves. The second waveform 108 can, however, to overcome this problemand penetrate through body tissue. The second waveform 112 can beapplied along with the first waveform 108 to an amplitude modulator 114,such as the modulator having the designation On-Semi MC1496, which issold by Texas Instruments.

The modulator 114 can be configured to generate a modulated waveform 116that is transmitted through a lead 118 to one or more electrodes 120.Four electrodes are illustrated, but the device 100 can include anynumber of electrodes having any size and shape. The lead 118 can beflexible, as in the illustrated embodiment. The electrodes 120 can beconfigured to, in turn, apply the modulated waveform 116 to a targetnerve 122 to stimulate the target nerve 122. As illustrated in FIGS. 15and 16, the first waveform 108 can be a square wave, and the secondwaveform 112 can be a sinusoidal signal. As will be appreciated by aperson skilled in the art, modulation of the first waveform 108 with thesecond waveform 112 can result in a modulated waveform or signal 116having the configuration shown in FIG. 11.

If an electrode is implanted under a patient's skin, a waveformtransmitted to the implanted electrode can include a modulating signalbut not include a carrier signal because, if the implanted electrode issufficiently near a BAT depot, the modulating signal alone can besufficient to stimulate the target. The waveform transmitted to animplanted electrode can, however, include both a modulating signal and acarrier signal.

Various exemplary embodiments of devices configured to directly apply anelectrical signal to stimulate nerves are described in more detail inU.S. Pat. Pub. No. 2005/0177067 filed Jan. 26, 2005 and entitled “SystemAnd Method For Urodynamic Evaluation Utilizing Micro-ElectronicMechanical System,” U.S. Pat. Pub. No. 2008/0139875 filed Dec. 7, 2006and entitled “System And Method For Urodynamic Evaluation UtilizingMicro Electro-Mechanical System Technology,” U.S. Pat. Pub. No.2009/0093858 filed Oct. 3, 2007 and entitled “Implantable PulseGenerators And Methods For Selective Nerve Stimulation,” U.S. Pat. Pub.No. 2010/0249677 filed Mar. 26, 2010 and entitled “PiezoelectricStimulation Device,” U.S. Pat. Pub. No. 2005/0288740 filed Jun. 24, 2004and entitled, “Low Frequency Transcutaneous Telemetry To ImplantedMedical Device,” U.S. Pat. No. 7,599,743 filed Jun. 24, 2004 andentitled “Low Frequency Transcutaneous Energy Transfer To ImplantedMedical Device,” U.S. Pat. No. 7,599,744 filed Jun. 24, 2004 andentitled “Transcutaneous Energy Transfer Primary Coil With A High AspectFerrite Core,” U.S. Pat. No. 7,191,007 filed Jun. 24, 2004 and entitled“Spatially Decoupled Twin Secondary Coils For Optimizing TranscutaneousEnergy Transfer (TET) Power Transfer Characteristics,” and European Pat.Pub. No. 377695 published as International Pat. Pub. No. WO1989011701published Nov. 30, 2004 and entitled “Interrogation And Remote ControlDevice.”

In use, at least one electrode of an implantable electrical stimulationdevice can be placed in the area of a BAT depot and be coupled to asignal generator. As will be appreciated by a person skilled in the art,the signal generator can have a variety of sizes, shapes, andconfigurations, and can be external to the patient or implanted thereinsimilar to a cardiac pacemaker. The signal generator can create theelectrical signal to be delivered to the BAT and can be on continuouslyonce activated, e.g., manually, automatically, etc. The signal generatorcan be in electronic communication with a device external to thepatient's skin to turn it on and off, adjust signal characteristics,etc. The external device can be positioned near the patient's skin,e.g., using a belt, a necklace, a shirt or other clothing item,furniture or furnishings such as a chair or a pillow, or can be adistance away from the patient's skin, such as a source locatedelsewhere in the same room or the same building as the patient. Theelectrical stimulation device can include circuitry configured tocontrol an activation distance, e.g., how close to a power source theelectrical stimulation device must be to be powered on and/or begindelivering electrical signals. Correspondingly, the external device caninclude a transmitter configured to transmit a signal to the electricalstimulation device's circuitry. If implanted, the signal generator caninclude an internal power source, e.g., a battery, a capacitor,stimulating electrodes, a kinetic energy source such as magnetspositioned within wired coils configured to generate an electricalsignal within the coils when shaken or otherwise moved, etc. In oneembodiment, a battery can include a flexible battery, such as a Flexionbattery available from Solicore, Inc. of Lakeland, Fla. In anotherembodiment, a battery can include an injectable nanomaterial battery.The power source can be configured to be recharged by transcutaneousmeans, e.g., through transcutaneous energy transfer (TET) or inductivecoupling coil, and/or can be configured to provide power for an extendedperiod of time, e.g., months or years, regardless of how long the powersource is intended to provide power to the device. In some embodiments,a power source can be configured to provide power for less than anextended period of time, e.g., about 7 days, such as if a battery isreplaceable or rechargeable and/or if device real estate can beconserved using a smaller, lower power battery. In some embodiments, thesignal generator can include an electrode patch onboard configured togenerate a pulse, thereby eliminating a need for a battery.

The signal generator, and/or any other portion of the device or externaldevice, as will be appreciated by a person skilled in the art, can beconfigured to measure and record one or more physical signals relatingto the activation of BAT. For non-limiting example, the physical signalscan include voltage, current, impedance, temperature, time, moisture,salinity, pH, concentration of hormones or other chemicals, etc. Therecorded physical signals can be presented to the patient's physicianfor evaluation of system performance and efficacy of brown adiposeactivation. Also, the recorded physical signals can be used in aclosed-loop feedback configuration to allow the device, e.g., thecontroller, to dynamically adjust the electrical signal settings usedfor treatment.

The devices disclosed herein can be designed to be disposed of after asingle use, or they can be designed to be used multiple times. In eithercase, however, the device can be reconditioned for reuse after at leastone use. Reconditioning can include any combination of the steps ofdisassembly of the device, followed by cleaning or replacement ofparticular pieces, and subsequent reassembly. In particular, the devicecan be disassembled, and any number of the particular pieces or parts ofthe device can be selectively replaced or removed in any combination.Upon cleaning and/or replacement of particular parts, the device can bereassembled for subsequent use either at a reconditioning facility, orby a surgical team immediately prior to a surgical procedure. Thoseskilled in the art will appreciate that reconditioning of a device canutilize a variety of techniques for disassembly, cleaning/replacement,and reassembly. Use of such techniques, and the resulting reconditioneddevice, are all within the scope of the present application.

Preferably, the invention described herein will be processed before use.First, a new or used instrument is obtained and if necessary cleaned.The instrument can then be sterilized. In one sterilization technique,the instrument is placed in a closed and sealed container, such as aplastic or TYVEK bag. The container and instrument are then placed in afield of radiation that can penetrate the container, such as gammaradiation, x-rays, or high-energy electrons. The radiation killsbacteria on the instrument and in the container. The sterilizedinstrument can then be stored in the sterile container. The sealedcontainer keeps the instrument sterile until it is opened in the medicalfacility.

It is preferred that device is sterilized. This can be done by anynumber of ways known to those skilled in the art including beta or gammaradiation, ethylene oxide, steam, and a liquid bath (e.g., cold soak).An exemplary embodiment of sterilizing a device including internalcircuitry is described in more detail in U.S. Pat. Pub. No. 2009/0202387filed Feb. 8, 2008 and entitled “System And Method Of Sterilizing AnImplantable Medical Device.”

One skilled in the art will appreciate further features and advantagesof the invention based on the above-described embodiments. Accordingly,the invention is not to be limited by what has been particularly shownand described, except as indicated by the appended claims. Allpublications and references cited herein are expressly incorporatedherein by reference in their entirety.

What is claimed is:
 1. A medical device, comprising: a stimulationdevice including an electrode configured to be transcutaneously appliedto a patient and to deliver an electrical signal to a depot of brownadipose tissue of the patient, a signal generator configured to generatethe electrical signal, a sensor configured to sense occurrence of atrigger event after the electrode has been applied to the patient, and acontroller, wherein when the sensor senses the trigger event and signalsthe sensed trigger event to the controller, the controller is configuredto cause the beginning of continuous delivery, via the electrode, of theelectrical signal to the patient having the electrode applied theretofor a period of time such that the depot of brown adipose tissue isactivated and energy expenditure thereof increases, wherein the periodof time is at least one day, and wherein the trigger event includes atleast one of a change in the patient's weight, a change in the patient'stissue impedance, and the patient sleeping.
 2. The medical device ofclaim 1, wherein the controller is pre-programmed with the period oftime such that the period of time is predetermined prior to thestimulation device being applied to the exterior skin surface.
 3. Themedical device of claim 1, wherein the period of time is less than fourweeks.
 4. The medical device of claim 1, wherein the stimulation deviceis configured to be applied to the patient and deliver the electricalsignal with at least a portion of the stimulation device attached to anexterior skin surface of the patient.
 5. The medical device of claim 1,wherein the electrical signal has a modulating signal and a carriersignal.
 6. The medical device of claim 1, wherein the electrical signalhas an activation signal pulse frequency in a range of 0.1 to 40 Hz andhas a pulse width in a range of 0.1 to 1 ms.
 7. The medical device ofclaim 1, further comprising a power source configured to supply power tothe signal generator.
 8. The medical device of claim 1, wherein thesignal generator is configured to receive power from a power supply thatis external to the patient and is off-board the stimulation device. 9.The medical device of claim 1, wherein the stimulation device includes apatch having a housing with the signal generator therein, and the patchis configured to be applied to an exterior skin surface of the patient.10. The medical device of claim 1, wherein the stimulation device isconfigured to be removed from the patient after the electrical signalhas been applied to the patient for the period of time and thenre-applied to the patient at a second, different depot of brown adiposetissue and to continuously deliver, via the electrode, a secondelectrical signal to the patient having the stimulation device appliedthereto at the second, different depot of brown adipose tissue for asecond period of time that is at least one day such that the seconddepot of brown adipose tissue is activated and energy expenditurethereof increases.